We use oxygen-15 water positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) as a marker of local neuronal activity in patients with schizophrenia and other neuropsychiatric disorders during performance of working memory and abstract reasoning tasks as well as during performance of matched sensorimotor control tests. In monozygotic twins discordant for schizophrenia, an area of the left inferior frontal gyrus corresponding to Brodmann's Areas 9 and 46 of the dorsolateral prefrontal cortex was lower in affected compared with unaffected twins during a frontal lobe-specific task which consistently activates this area in normal subjects. The left hippocampus and superior temporal gyrus, discriminated between affected and unaffected co-twins in each and every pair and was more active in each of the ill twins. We further localized this hyperfunctionality to the anterior (pes) portion of the hippocampal formation as opposed to more posterior hippocampal areas. The functional pattern in the amygdala, if anything, tends to be opposite, i.e. activity tends to be lower in schizophrenia. We have also shown that even when patients with schizophrenia are compared with young normal subjects with equally poor performance, they have diminished prefrontal cortical response while performing tasks with a strong working memory component. Moreover, patients with schizophrenia still show reduced activation of the prefrontal cortex when compared with healthy, elderly subjects matched with them on a one-to-one basis for WCST performance. In this schizophrenic group, reduced activation in the DLPFC correlated with more perseveration during the WCST. In contrast, in the elderly subjects DLPFC activation is preserved and does not correlate with performance, suggesting that other mechanisms may account for their cognitive impairment on this task. We have initiated a number of cross-modal neuroimaging studies in schizophrenia. We have found that prefrontal N-acetyl-aspartate magnetic resonance spectroscopy signal predicts impaired WCS rCBF activation not only in the prefrontal cortices of our patients, but also in other nodes in the working memory system. This relationship is not found in patients, but not in control subjects, and not with NAA in other brain regions for either group. In a study comparing IBZM binding (a SPECT measure that may reflect basal synaptic dopamine) with rCBF during working memory we found that dopamine receptor occupancy predicts hippocampal activation during working memory in schizophrenia.